Prediction of pathologic complete response to neoadjuvant chemoradiation in locally advanced rectal cancer.

Purpose: To investigate the predictive factors of pathologic complete response (pCR) in locally advanced rectal cancer (LARC) patients who had been treated with neoadjuvant chemoradiation (nCRT). Methods and materials: For this retrospective study, 53 LARC patients (37 males and 16 females; age range 25 to 79 years) were selected. Clinical characteristics, baseline mrTNM staging, MR gross tumor volumes (GTV), and pCR were evaluated. The diagnostic accuracy of GTV for predicting pCR was calculated. Results: Among 53 LARC patients, 15 patients achieved pCR (28.3%), while 38 patients achieved non-pCR. Only three (5.7%) out of 53 patients did not downstage after nCRT. GTV and tumor differentiation were the significant prognostic parameters for predicting pCR. A tumor volume threshold of 21.1 cm3 was determined as a predictor for pCR, with a sensitivity of 84% and specificity of 47%. In addition, GTV was associated with mrN stage, circumferential resection margin (CRM) status, extramural vascular invasion (EMVI) status, and pretreatment serum CEA level. Conclusion: Tumor volume and tumor differentiation have significant predictive values in preoperative assessment of pCR among LARC patients. These findings aid clinicians to discriminate those patients who may likely benefit from preoperative regimens and to make optimal treatment plans.

Longitudinal variation of serum PCSK9 in ulcerative colitis: association with disease activity, T helper 1/2/17 cells, and clinical response of tumor necrosis factor inhibitor.

AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates CD4+ T cell differentiation and inflammatory response, the latter ones mediate ulcerative colitis (UC) initiation. This study intended to explore the correlation of serum PCSK9 with disease activity, T helper (h)1/Th2/Th17 cells, and clinical response of tumor necrosis factor inhibitor (TNFi) in UC patients. METHODS: In 65 UC patients underwent TNFi treatment, serum PCSK9 was evaluated at baseline (W0), week (W)2, W6, and W12 by enzyme-linked immunosorbent assays; meanwhile, Th1/Th2/Th17 cells were determined at W0 by flow cytometry. Besides, serum PCSK9 was detected in 65 healthy controls (HCs). RESULTS: Serum PCSK9 was increased in UC patients compared to HCs (P<0.001), which also positively correlated with C-reactive protein (P=0.009), total Mayo score (P=0.018), Mayo-defined disease activity (P=0.020), Th1 (P=0.033), and Th17 (P=0.003) cells, but not Th2 cells (P=0.086) in UC patients. Interestingly, serum PCSK9 was steadily declined from W0 to W12 (P<0.001). W2-W0, W6-W0, and W12-W0 serum PCSK9 change (PCSK9 at W2, W6, or W12 minus PCSK9 at W0, respectively) was gradually becoming greater during TNFi treatment (P<0.001). Furthermore, forty-five (69.2%) patients achieved clinical response at W12, whose serum PCSK9 at W6 (P=0.041) and W12 (P=0.001) was lower, and W6-W0 (P=0.043), W12-W0 (P=0.019) serum PCSK9 change was more obvious compared to patients without clinical response at W12. CONCLUSIONS: Serum PCSK9 is positively related to disease activity, Th1, and Th17 cells in UC patients; further, its decline correlates with TNFi response achievement in these patients.

ESQmodel: biologically informed evaluation of 2-D cell segmentation quality in multiplexed tissue images.

MOTIVATION: Single cell segmentation is critical in the processing of spatial omics data to accurately perform cell type identification and analyze spatial expression patterns. Segmentation methods often rely on semi-supervised annotation or labeled training data which are highly dependent on user expertise. To ensure the quality of segmentation, current evaluation strategies quantify accuracy by assessing cellular masks or through iterative inspection by pathologists. While these strategies each address either the statistical or biological aspects of segmentation, there lacks a unified approach to evaluating segmentation accuracy. RESULTS: In this article, we present ESQmodel, a Bayesian probabilistic method to evaluate single cell segmentation using expression data. By using the extracted cellular data from segmentation and a prior belief of cellular composition as input, ESQmodel computes per cell entropy to assess segmentation quality by how consistent cellular expression profiles match with cell type expectations. AVAILABILITY AND IMPLEMENTATION: Source code is available on Github at: https://github.com/Roth-Lab/ESQmodel.

RNF43 mutation as a predictor of immunotherapeutic efficacy in colorectal cancer.

RNF43 is a tumor suppressor for various cancers and is considered to drive carcinogenesis when mutated. However, the correlation between RNF43 mutation and colorectal cancer (CRC) immunotherapy remains unreported. We evaluated the role of RNF43 using publicly available data from the Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC). In addition, further analysis was performed on an internal validation cohort (hcohort). The mutant profiles of RNF43 were analyzed in 873 Chinese CRC patients. The relationship between clinical pathologic features and RNF43 were analyzed using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics were associated with overall survival using Cox regression and the Kaplan-Meier method. We found that RNF43 mutation was significantly associated with high TMB and high MSI score (all p-values < 0.05) in the MSKCC cohort. Additionally, RNF43 mutation was found to be enriched in MSI instability. Kaplan-Meier survival analysis revealed that patients with RNF43 mutation had better OS compared to RNF43 wild-type (not reached vs. 13 months, HR, 0.12; 95% CI 0.03 to 0.49; P = 0.0034). However, no association was observed between RNF43 and OS in the TCGA cohort (HR, 1.83; 95% CI 0.66 to 5.07; P = 0.2479). Our CRC hcohort confirmed the significance of RNF43 mutation in predicting better clinical outcomes, including ORR (45% vs. 21%, P = 0.0468). RNF43 mutation correlated with a high tumor mutation burden (P < 0.001). The mutation frequency of RNF43 in CRC patients was 8.4% (73/873); RNF43 G659Vfs*41 was found to be the most frequent mutation site. In patients with RNF43 mutations, TP53, KRAS, and TGFBR2 were genes with a high frequency of mutations. Compared with RNF43 wild-type patients, those with RNF43 mutations had a higher TMB score and a greater proportion of MSI-H, but no difference in PD-L1 expression. Moreover, the content of immune-related B cells, CD8+ T cells, neutrophils, and dendritic cells was higher in the RNF43 mutant group than in the wild-type group. Our results suggest that RNF43 mutation may correlate with better OS in CRC patients receiving PD-1/PD-L1 inhibitors. The exact mechanisms underlying RNF43 require further investigation.

Black Phosphorus/Ferroelectric P(VDF-TrFE) Field-Effect Transistors with High Mobility for Energy-Efficient Artificial Synapse in High-Accuracy Neuromorphic Computing.

The neuromorphic system is an attractive platform for next-generation computing with low power and fast speed to emulate knowledge-based learning. Here, we design ferroelectric-tuned synaptic transistors by integrating 2D black phosphorus (BP) with a flexible ferroelectric copolymer poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)). Through nonvolatile ferroelectric polarization, the P(VDF-TrFE)/BP synaptic transistors show a high mobility value of 900 cm2 V-1 s-1 with a 103 on/off current ratio and can operate with low energy consumption down to the femtojoule level (∼40 fJ). Reliable and programmable synaptic behaviors have been demonstrated, including paired-pulse facilitation, long-term depression, and potentiation. The biological memory consolidation process is emulated through ferroelectric gate-sensitive neuromorphic behaviors. Inspiringly, the artificial neural network is simulated for handwritten digit recognition, achieving a high recognition accuracy of 93.6%. These findings highlight the prospects of 2D ferroelectric field-effect transistors as ideal building blocks for high-performance neuromorphic networks.

Expression Profiles, Prognosis, and ceRNA Regulation of SRY-Related HMG-Box Genes in Stomach Adenocarcinoma.

Aberrant expression of the SRY-related HMG-box (SOX) genes contributes to tumor development and progression. This research aimed to identify the regulation of the SOX genes in stomach adenocarcinoma (STAD). Expression profiles downloaded from The Cancer Genome Atlas (TCGA) were conducted to analyze the expression and function of the SOX genes. A competing endogenous RNAs (ceRNA) network mediated by the SOX genes was effectively constructed consisting of 64 lncRNAs, 29 miRNAs, and 11 SOX genes based on predicted miRNAs shared by lncRNAs and mRNAs using miRDB, TargetScan, miRTarBase, miRcode, and starBase v2.0. SOX9 was identified as a prognostic signature, which showed the usefulness of diagnosis and prognosis of STAD by the receiver operating characteristic (ROC) and Kaplan-Meier curves. SOX9 was also shown specifically in STAD and identified as highly expressed in the gastrointestinal tract. Gene Ontology (GO) enrichment analysis showed that SOX9 might influence the genes related to the pattern specification process, sodium ion homeostasis, and potassium ion transport, mainly including FEZF1, HOXC13, HOXC10, HOXC9, HOXA11, DPP6, ATP4B, CASQ2, KCNA1, ATP4A, and SFRP1. Furthermore, HOTAIR knockdown, miR-206-mimic transfection, the Cell Count Kit-8 (CCK-8) assay were performed to verify the function of HOTAIR/miR-206/SOX9 axis, which was identified in the ceRNA network analysis. HOTAIR could induce proliferation potentially by competitively binding miR-206/SOX9 axis in STAD. These findings provide new clues with prognostic and therapeutic implications in STAD and suggest that HOTAIR/miR-206/SOX9 might be a potential new strategy for therapeutic targeting of gastric cancer.

KIF4 enforces the progression of colorectal cancer by inhibiting the autophagy via activating the Hedgehog signaling pathway.

This work firstly scrutinized the effect of KIF4 on the progression of CRC. KIF4 expression in CRC clinical tissues and cells was evaluated by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Cell counting kit-8 assay, Transwell invasion and migration assay were implemented to research the function of KIF4 on the proliferation, invasion and migration of CRC cells. The effect of KIF4 on the autophagy and the Hedgehog pathway activityavtivity in CRC cells was explored in the presence or absence of rapamycin and ring propylamine. The expression of autophagy-related proteins was scrutinized by qRT-PCR, Western blot and immunofluorescence. Autophagosomes in CRC cells was observed by transmission electron microscopy. In vivo xenograft experiment was executed. Immunohistochemistry of xenograft tumor tissues was executed to investigate the Hedgehog pathway activityactivtiy. KIF4 was abundantly expressed in CRC clinical tissues and cells. KIF4 enforced the proliferation, invasion, migration of CRC cells, repressed the autophagy and activated the Hedgehog pathway in CRC cells. Rapamycin and ring propylamine treatment reversed the inhibition of KIF4 on the autophagy and the promotion of KIF4 on the Hedgehog pathway activity in CRC cells. Ring propylamine treatment reversed the inhibition of KIF4 on the autophagy in CRC cells. KIF4 intensified the in vivo growth of CRC cells and activated the Hedgehog pathway in xenograft tumor tissues. KIF4 acted as an oncogene in CRC by inhibiting the autophagy via activating the Hedgehog pathway. It might be a potential target for CRC treatment.

Impact of Previous Local Treatment for Brain Metastases on Response to Molecular Targeted Therapy in BRAF-Mutant Melanoma Brain Metastasis: A Systematic Review and Meta-Analysis.

Background: Melanoma brain metastases (BMs) are associated with poor prognosis and are the main cause of mortality in melanoma patients. BRAF inhibitors have shown intracranial activity in both treatment-naïve and previously treated BM patients. We aimed to investigate if there was any difference in response of BRAF inhibitors in these two cohorts. Materials and Methods: Electronic database search included PubMed, Medline, and Cochrane library until March 2021 for studies with desired comparative outcomes. Outcomes of interest that were obtained for meta-analysis included intracranial response rate as the primary outcome and survival and safety outcomes as the secondary outcomes. Review Manager version 5.4 was used for data analysis. Results: Three studies comprising 410 BRAF-mutated melanoma patients with BMs were included according to eligibility criteria. The comparative cohort included patients with treatment-naïve BMs (TN cohort; n = 255) and those who had progressive disease after receiving local brain treatment for BMs (PT cohort; n = 155). Meta-analysis revealed that BRAF inhibitors (vemurafenib and dabrafenib) and BRAF/MEK inhibitor combination (dabrafenib and trametinib) induced significantly higher intracranial disease control (OR 0.58 [95% CI: 0.34, 0.97], p = 0.04) and a trend toward improved progression-free survival (PFS) (HR 1.22 [95% CI: 0.98, 1.52], p = 0.08) in the PT cohort as compared to the TN cohort. Overall survival was not significantly different between the cohorts (HR 1.16 [95% CI: 0.89, 1.51], p = 0.28). Subgroup analysis revealed that PFS was significantly improved (HR 1.67 [95% CI: 1.06, 2.62], p = 0.03), and a trend toward improved OS (HR 1.62 [95% CI: 0.95, 2.75], p = 0.08) was achieved in patients receiving BRAF/MEK inhibitor combination and patients with BRAFv600K mutation receiving dabrafenib alone. No increase in overall adverse events (AEs), grade 3/4 AEs, and severe adverse events (SAEs) was observed between the cohorts. Conclusions: BRAF inhibitors (plus MEK inhibitor) may achieve better intracranial disease stability in BRAF-mutant melanoma patients who have received previous local treatment for BMs. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/), identifier CRD42020185984.

Hap-pulse: A Wearable Vibrotactile Glove for Medical Pulse Wave Rendering.

Pulse palpation is an important procedure that allows a physician to rapidly assess the status of a patient's cardiovascular system. This paper explores the possibility of using vibrotactile stimuli to render fine temporal profiles of pulse pressure waves. A lightweight wearable vibrotactile glove, called Hap-pulse, is designed to render fine pulse waves through vibrotactile stimuli on users' fingertips. To preserve the fine features of original pulse waves, models are fitted from real pulse wave data (photoplethysmogram (PPG) pulse waveform database), using fourth-order polynomial functions. A square wave envelope mapping algorithm is proposed to produce vibration amplitudes of Linear Resonance Actuators (LRAs), which aims to render the detailed waveform of systolic and diastolic blood pressure states. Evaluation results suggest that Hap-pulse can render pulse waves with an average correlation coefficient 97.84%. To validate the distinguishability and fidelity of Hap-pulse's palpation rendering, a user study consisting of traditional Chinese medicine doctors and unskilled students is conducted. The correct recognition rate of identifying four typical pulse waves is 87.08% (doctors), 57.50% (untrained students) and 79.59% (trained students). These results indicate a novel application of rendering subtle pulse wave signals with vibrotactile gloves, which illustrates the potential of simulating patient palpation training in virtual or remote medical diagnosis.

Soluble PD-1: Predictive, Prognostic, and Therapeutic Value for Cancer Immunotherapy.

Programmed death protein 1 (PD-1) interaction with PD-L1 deliver immunosuppressive environment for tumor growth, and its blockade with directed monoclonal antibodies (anti-PD-1/anti-PD-L1) has shown remarkable clinical outcome. Lately, their soluble counterparts, sPD-1 and sPD-L1, have been detected in plasma, and elevated levels have been associated with advanced disease, clinical stages, and worst prognosis for cancer patients. Elevated plasma levels of sPD-L1 have been correlated with worst prognosis in several studies and has displayed a persistent outlook. On the other hand, sPD-1 levels have been inconsistent in their predictive and prognostic ability. Pretherapeutic higher sPD-1 plasma levels have shown to predict advanced disease state and to a lesser extent worst prognosis. Any increase in sPD-1 plasma level post therapeutically have been correlated with improved survival for various cancers. In vitro and in vivo studies have shown sPD-1 ability to bind PD-L1 and PD-L2 and block PD-1/PD-L1 interaction. Local delivery of sPD-1 in cancer tumor microenvironment through local gene therapy have demonstrated an increase in tumor specific CD8+ T cell immunity and tumor growth reduction. It had also exhibited enhancement of T cell immunity induced by vaccination and other gene therapeutic agents. Furthermore, it may also lessen the inhibitory effect of circulating sPD-L1 and enhance the effects of mAb-based immunotherapy. In this review, we highlight various aspects of sPD-1 role in cancer prediction, prognosis, and anti-cancer immunity, as well as, its therapeutic value for local gene therapy or systemic immunotherapy in blocking the PD-1 and PD-L1 checkpoint interactions.

Effects of soluble dietary fiber from soybean residue fermented by Neurospora crassa on the intestinal flora in rats.

In this study, soluble dietary fiber (SDF, including oligosaccharides and polysaccharides) of soybean residue (SR) fermented by Neurospora crassa was used as a research object. In vitro fermentation technology was used to analyze the fermentation properties of SDF from fermented soybean residue (FSR). Moreover, the effects of SDF from FSR on the composition and diversity of intestinal microflora of rats were studied by high-throughput sequencing technology. Results showed that the SDF content of fermented soybean residue was 27.21%. The addition of SDF in the range 2 to 10 g L-1 could increase the levels of gas production and short-chain fatty acids (SCFAs), as well as decrease the pH and ammonia N concentration after 24 h fermentation in the fermentation broth compared with the control group (p < 0.05). The animal-based experiments showed that Bacteroidetes and Firmicutes were the major dominant phyla in all the groups. Compared with the control group, oligosaccharides and polysaccharides of FSR changed the relative abundance and diversity of the bacterial community, and increased the numbers of beneficial flora, such as Prevotellaceae and Lactobacillales. It was shown that SDF of SR fermented by Neurospora crassa had great effects on the intestinal environment and the composition of intestinal flora in rats.

MiR-107 function as a tumor suppressor gene in colorectal cancer by targeting transferrin receptor 1.

BACKGROUND: While microRNAs (miRNAs) are known to play a critical role in the progression of colorectal cancer, the role of miR-107 remains unknown. We evaluated its role and explored the underlying mechanism. MATERIALS & METHODS: MTT, wound-healing, transwell migration and transwell invasion assays were performed to evaluate the role of miR-107 in SW629 cell proliferation, migration and invasion. Real time-PCR and dual-luciferase reporter gene, TFR1 overexpression and western blotting assays were used to explore the underlying mechanism. RESULTS: MiR-107 is downregulated in colorectal cancer tissues and several human colorectal cancer cell lines. Low miR-107 expression often indicates a poor survival rate for colorectal cancer patients. MiR-107 suppresses the proliferation, migration and invasion of SW620 cells by negatively regulating transferrin receptor 1 (TFR1). CONCLUSION: MiR-107 suppresses the metastasis of colorectal cancer and could be a potential therapy target in colorectal cancer patients.

Spatial-Resolution Cell Type Proteome Profiling of Cancer Tissue by Fully Integrated Proteomics Technology.

Increasing attention has been focused on cell type proteome profiling for understanding the heterogeneous multicellular microenvironment in tissue samples. However, current cell type proteome profiling methods need large amounts of starting materials which preclude their application to clinical tumor specimens with limited access. Here, by seamlessly combining laser capture microdissection and integrated proteomics sample preparation technology SISPROT, specific cell types in tumor samples could be precisely dissected with single cell resolution and processed for high-sensitivity proteome profiling. Sample loss and contamination due to the multiple transfer steps are significantly reduced by the full integration and noncontact design. H&E staining dyes which are necessary for cell type investigation could be selectively removed by the unique two-stage design of the spintip device. This easy-to-use proteome profiling technology achieved high sensitivity with the identification of more than 500 proteins from only 0.1 mm2 and 10 µm thickness colon cancer tissue section. The first cell type proteome profiling of four cell types from one colon tumor and surrounding normal tissue, including cancer cells, enterocytes, lymphocytes, and smooth muscle cells, was obtained. 5271, 4691, 4876, and 2140 protein groups were identified, respectively, from tissue section of only 5 mm2 and 10 µm thickness. Furthermore, spatially resolved proteome distribution profiles of enterocytes, lymphocytes, and smooth muscle cells on the same tissue slices and across four consecutive sections with micrometer distance were successfully achieved. This fully integrated proteomics technology, termed LCM-SISPROT, is therefore promising for spatial-resolution cell type proteome profiling of tumor microenvironment with a minute amount of clinical starting materials.